Cyanide can be treated with poppers

vivianimbriotis | March 20, 2025, 5:43 p.m.

Not jalapeno poppers - poppers as in inhaled nitrates, a party drug and iconographic substance among certain elements of the queer community (induces lightheadedness and smooth muscle relaxation, including of certain relevant sphincter muscles).

Maybe if you're confused about carbon monoxide or methaemaglobin, this might also help clarify a few things.

Iron is an atom

Iron is an element with atomic number 26. In metallic form, it has an electron configuration like this:

1s2 (filled)

2s2 (filled)

2p6 (filled)

3s2 (filled)

3d6 (filled)

4s2 (filled)

3d6 (out of 10)

Or, for brevity, [Ar] 4s2 3d6

It has two common ionization states. In the ferrous state, with 2+ charge, it loses its two 4s2 electrons, giving it a configuration of [Ar] 3d6.

But that 3d6 orbital is not very stable - it would be most stable if filled, but failing that it would at least like to be half-filled i.e. 3d5. So Iron(III), the ferric form, is more energetically stable, with configuration [Ar] 3d5.

Haem is a molecule

Heme is a molecule made of a porphyrin ring with an iron molecule in the center. This iron molecule forms 2 kinds of bonds:

1. Traditional \(\sigma\) bonds with two of the surrounding nitrogens (in which both particles share an electron - this is a traditional electron-sharing bond and refills the 4s2 orbital
2. Dative bonds between 2 more nitrogens, a histidine residue below, and another particle above, resulting in an octahedral coordination structure.

Haemoglobin is a protein, carbon monoxide a gas

Haemoglobin is a protein containing four heme molecules, which are non-covalently nestled in the protein structure. The haems are all in Fe(II) state, allowing them to bond either a water or a dioxygen molecule in that top-most position.

As you can see in the picture above, when Fe(II) haem bonds an oxygen (displacing a water), it is pulled upwards, changing the haem from a bowl-shape into a planar molecule. This tugs on the histidine residue at the bottom, causing a conformational change that increases the affinity for the other haem residues in the haemoglobin.

When all the haems bind water, the haemoglobin is "deoxyhaemoglobin", and is in "Tense state" or "T state", with low oxygen affinity. When all four bind oxygen, it is "oxyhaemoglobin", in "Relaxed" or "R state", with very high oxygen affinity. This is part of the cause of the sigmoid oxygen-haemoglobin dissociation curve.

The oxygen bond to Fe(II) haem is relatively weak, because it needs to be broken in the peripherries - there's no use to binding oxygen irreversibly, that doesn't help with gas exchange at all! But one other species does bind very strongly to Fe(II) haem in haemoglobin - carbon monoxide gas.

If enough binding sites are occupied by CO, there will be no ability to bind O2 and resultant hypoxia. Cranking the partial pressure of O2 will help in displacing the CO from it's binding site, compensating for relatively low affinity with relatively high chemical activity.

Methaemaglobin is the Waluigi of the blood

Methaemaglobin is haemaglobin where one or more of the haems has been oxidized from the \(Fe^{2+}\) to the \(Fe^{3+}\) form.

Fe(III) haem cannot bind oxygen. This is because it is more positively charged now, and it can't settle for a coordination bond - it needs a proper goddamn anion, so it makes it's own, ripping a proton off a water molecule to make OH- and binding that in the top position with high affinity. No oxygen allowed.

But in the case of haemoglobin, things are even worse - because Fe(III) haem is conformationally different to Fe(II) haem, and even one oxidized haem will lock the whole molecule in the R state, with high oxygen affinity. This means the remaining Fe(II) haems can't drop their oxygen off in the peripheries!

Remember the Fe(III) is more stable than Fe(II), so haem converted to Fe(III) form tends to stay that way until it is actively reduced.

Methaemaglobin can be reduced by the body's natural methaemaglobin reductase, an enzyme that catalyzses the reduction of methaemoglobin by NADPH. People with a deficiency of G6PD can't make much NADPH, so they generally can't reduce their methaemoglobin back to haemoglubin efficiently. Those are the sample people that get a haemolytic anaemic when exposed to oxidative stress (like eating broad beans / fava beans).

Strong oxidizers induce methaemaglobinaemia through a redox reaction

1. Nitrates
2. Glyceryl trinitrate
3. Isosorbide mononitrate
4. Amyl or isobutyl nitrate ("poppers")
5. Inhaled nitric oxide
6. Dapsone

We can treat methaemaglobinaemia by administering a strong reducing agent like ascorbic acid, or by giving them lots of oxygen to compensate.

Alternatively, we can give them methylene blue. Methylene blue is a pretty dye. When given IV, it basically acts like a superchaged methaemaglobin reductase, allowing a person's own NADPH stores to rapidly reduce their methaemaglobin:

1. NADPH reduces methylene blue (MB) to leukomethylene blue (LMB)
2. LMB reduces metHb to Hb (LMB is oxidized back to MB)

If someone has G6PD deficiency and has very low stores of NADPH, giving them methylene blue might protentiate an oxidative crisis where they have no antioxidant left in their red cells, causing haemolysis.

Cyanide is a poision treated with poppers

Elsewhere in the body, the oxidation and reduction of haem is exploited by physiology. In the mitochondria, a series of haem-bearing proteins form the electron transport chain. Each one of them has a Fe(III) haem with increasing oxidation potential. An electron is 'carried' along the chain as each complex in turn gets reduced to Fe(II) form, and then oxidized by the next protein in the sequence back to Fe(III) form.

$$e^- + Fe(III) + Fe(III) + Fe(III)$$

$$Fe(II) + Fe(III) + Fe(III)$$

$$Fe(III) + Fe(II) + Fe(III)$$

$$Fe(III) + Fe(III) + Fe(II)$$

$$Fe(III) + Fe(III) + Fe(III) + e^-$$

The movement of this electron from species to species, each a decreasing energy state, generates work that is used to pump hydrogen ions out of the mitochondria. Those ions then power the Great Pump that grinds together ADP and phosphate to make ATP.

Cyanide is a nitrogen and carbon joined by a triple bond. It cannot bind to Fe(II) haem, but it binds incredibly strongly to Fe(III) haem via something called pi back-bonding. The richest source of Fe(III) haem is these electron transport chain proteins. Cyanide binds to them in that top-most position in place of OH-, and in so doing locks them into the Fe(III) oxidation state. Now they can't carry an electron, so no matter how much oxygen is around, none of it can be used to fuel the electron transport chain.

Of course, if there's methaemoglobin around, that's Fe(III) haem as well...so cyanide can bind to that instead. So the old-school treatment for cyanide poising is to induce a methaemaglobinaemia - that's why inhalded amyl nitrate (yes, that's poppers) is a treatment for cyanide poisoning.

Another treatment is vitamin B12. That's not iron(III) haem! But it almost is. Vitamin B12 is a coordination complex built around a cobalt, which is in a 3+ oxidation state with an octahedral coordination structure, with 5 of the 6 coordination sites occupied by nitrogens. Look at the similarities to haem:

And you KNOW that cyanide wants to bind right up at that top coordinating bond.

Where might you aquire some of this poison? Well, one common place would be sodium nitroprusside, a lovely red substance that is basically five cyanides and a nitric oxide coordinating octahedrally with an iron:

This binds to haemoglobin, coverts it to methaemoglobin, binds the cyanide to the mathaemoglobin, and liberates the nitric oxide to cause vasodilation (which is the only bit that is intended, all that other stuff is a side effect).